This invention relates to novel utilities for derivatives of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid that have previously been disclosed to be useful for the treatment of hypertension in U.S. Pat. No. 4,812,462 to Blankley et al, issued March 14, 1989. These compounds have the property of antagonizing the binding of angiotensin II (angiotensin II), a peptide hormone, to one subtype of its cellular receptors. In particular, the utility of these compounds arises from activity at the AT.sub.2 receptor as described by Bumpus, et al, in Hypertension, 1991, 17, 720-721.
The present invention is related to the discovery that the AT.sub.2 receptor is found in the central nervous system (CNS) of mammals, and that compounds of general Formula I described herein are effective in blocking angiotensin II binding at AT.sub.2 receptors in various brain regions. The present invention is also related to the discovery that alterations in brain biochemistry are observed upon administration of compounds of general Formula I and that these alterations coincide with physiological and behavioral responses.
The present invention is also related to the discovery that AT.sub.2 receptors are found in female reproductive organs of mammals including uterus (Data in Table 1, hereof and in Dudley, et al, Molecular Pharmacol., 1990, 38, 370-377) and ovaries (Pucell, et al, Endocrinology, 1991, 128, 1947-59). The role of angiotensin II in processes leading to ovulation has been reviewed by Andrade-Gordon, et al, in Biochemical Pharmacology, 1991, 42, 715-719. Compounds of general Formula I, inhibit the binding of angiotensin II to AT.sub.2 receptors in reproductive tissues, including uterus and ovarian follicles and hence antagonize the effects of angiotensin II therein.
Finally, the present invention is related to the discovery that the AT.sub.2 receptor is found in neuronal tumor cells (Speth, et al, Peptide Research, 1989, 2, 232-239) and in transformed human neural cells (Tallant, et al, Hypertension, 1991, 17, 1135-1143).